Summary: Breast cancer is the most prevalent cancer and the second leading cause of cancer-related death in women in the United States. However, little progress has been made in preventing the incidence of breast cancer. Most breast cancer mortality results from metastatic recurrence after initial success of surgery and/or other therapies. Although extended treatment with selective estrogen receptor modulators and aromatase inhibitors have been proven effective in preventing metastatic recurrence of breast cancer, the benefit is limited to ER+ breast cancer, and severe adverse effects make them suboptimal for long-term use. Currently there are no preventive agents for ER- breast cancer. This is of particular relevance given the high metastatic recurrence rate and the resulting poor prognosis of triple negative breast cancer. One common feature of breast cancer, regardless of the subtypes, is the pro-tumor nature of the tumor microenvironment, which contains abundant M?s, called tumor-associated macrophages (TAMs). TAMs promote tumor development and metastasis through inducing immunosuppression, promoting angiogenesis, enhancing tumor cell proliferation and invasiveness, and facilitating cancer stem cell (CSC) formation and maintenance. Due to their determinant roles in all stages of cancer development, TAMs have been considered as a therapeutic target for cancer. However, M?s have not yet been exploited as a target for breast cancer prevention. Emodin is a small molecule compound derived from many plants including several Chinese herbs. Our published studies showed that emodin inhibited breast cancer growth and metastasis in orthotopic mouse models through reducing M? recruitment to tumors and lungs and suppressing their M2-like polarization by acting on both M?s and breast cancer cells. Our preliminary studies further showed that emodin could suppress TGF?1-induced epithelial to mesenchymal transition and diminish the stemness of breast cancer cells, and reduce the death due to metastatic recurrence after surgical removal of primary tumors in an orthotopic breast cancer model. Importantly, a comprehensive NIH toxicology study showed that emodin is very safe for long-term use in mice and rats. Given the important roles of M?s in breast cancer initiation and metastatic recurrence, and based on our published and preliminary data, we hypothesize that emodin can be developed as a safe and effective chemopreventive agent for breast cancer incidence and metastatic recurrence by virtue of its ability to block the tumor-promoting crosstalk between cancer cells and M?s. Two specific aims are proposed: SA1. To determine the effects of emodin on preventing breast cancer onset and post-surgery metastatic recurrence in mouse models; and SA2. To elucidate the mechanisms by which emodin prevents breast cancer onset and metastatic recurrence. The success of the proposed preclinical studies will set a stage for clinical trials to develop emodin as a new safe, effective and low-cost chemopreventive agent for breast cancer regardless of the subtype.